The present invention relates to pharmacologically active compounds and to their use as medicaments. More particularly it has been found that the sterol derivatives of the invention are useful for regulating meiosis.
Meiosis is the unique and ultimate event of germ cells on which sexual reproduction is based. Meiosis comprises two meiotic divisions. During the first division, exchange between maternal and paternal genes take place before the pairs of chromosomes are separated into the two daughter cells. These contain only half the number (1n) of chromosomes and 2c DNA. The second meiotic division proceeds without a DNA synthesis. This division therefore results in the formation of the haploid germ cells with only 1c DNA.
The meiotic events are similar in the male and female germ cells, but the time schedule and the differentiation processes which lead to ova and to spermatozoa differ profoundly. All female germ cells enter the prophase of the first meiotic division early in life, often before birth, but all are arrested as oocytes later in the prophase (dictyate state) until ovulation after puberty. Thus, from early life the female has a stock of oocytes which is drawn upon until the stock is exhausted. Meiosis in females is not completed until after fertilization, and results in only one ovum and two abortive polar bodies per germ cell. In contrast, only some of the male germ cells enter meiosis from puberty and leave a stem population of germ cells throughout life. Once initiated, meiosis in the male cell proceeds without significant delay and produces four spermatozoa.
Only little is known about the mechanisms which control the initiation of meiosis in the male and in the female. In the oocyte, new studies indicate that follicular purines, hypoxanthine or adenosine, could be responsible for meiotic arrest (Downs, S M et al. Dev Biol 82 (1985) 454-458; Eppig, J J et al. Dev Biol 119 (1986) 313-321; and Downs, S M Mol Reprod Dev 35(1993) 82-94).
The instant invention provides compounds and methods useful for relieving infertility in females and males, particularly in mammals, more particularly in humans. These compounds and methods are useful as contraceptives in females and males, particularly in mammals, more particularly in humans. Further, methods are described for using the instant compounds for regulating meiosis in oocytes and in male germ cells.
In its broadest aspect, the present invention relates to compounds of formula (I) 
wherein R1 and R2, independently, are selected from the group consisting of hydrogen and branched or unbranched C1-C6 alkyl which may be substituted by halogen, hydroxy or cyano, or wherein R1 and R2 together designate methylene or, together with the carbon atom to which they are bound, form a cyclopropane ring, a cyclopentane ring, or a cyclohexane ring; R3 is selected from the group consisting of hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, xe2x95x90NOR26 wherein R26 is hydrogen or C1-C3 alkyl, halogen, and hydroxy and C1-C4 alkyl bound to the same carbon atom of the sterol skeleton, or designates, together with R9 or R14, an additional bond between the carbon atoms to which R3 and R9 or R14 are bound; R4 is selected from the group consisting of hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, xe2x95x90NOR27 wherein R27 is hydrogen or C1-C3 alkyl, halogen, and hydroxy and C1-C4 alkyl bound to the same carbon atom of the sterol skeleton, or R4 designates, together with R13 or R15, an additional bond between the carbon atoms to which R4 and R13 or R15 are bound; R5 is selected from the group consisting of hydrogen, C1-C4 alkyl, methylene, hydroxy, methoxy, oxo, and xe2x95x90NOR22 wherein R22 is hydrogen or C1-C3 alkyl, or R5 designates, together with R6, an additional bond between the carbon atoms to which R5 and R6 are bound; R6 is hydrogen or R6 designates, together with R5, an additional bond between the carbon atoms to which R5 and R6 are bound; R9 is hydrogen or R9 designates, together with R3 or R10, an additional bond between the carbon atoms to which R9 and R3 or R10 are bound; R10 is hydrogen or R10 designates, together with R9, an additional bond between the carbon atoms to which R10 and R9 are bound; R11 is selected from the group consisting of hydroxy, alkoxy, substituted alkoxy, acyloxy, sulphonyloxy, phosphonyloxy, oxo, xe2x95x90NOR28 wherein R28 is hydrogen or C1-C3 alkyl, halogen and hydroxy and C1-C4 alkyl bound to the same carbon atom of the sterol skeleton, or R11 designates, together with R12, an additional bond between the carbon atoms to which R11 and R12 are bound; R12 is selected from the group consisting of hydrogen, C1-C3 alkyl, vinyl, C1-C3 alkoxy and halogen, or R12 designates, together with R11, an additional bond between the carbon atoms to which R12 and R11 are bound; R13 is hydrogen or R13 designates, together with R4 or R14, an additional bond between the carbon atoms to which R13 and R4 or R14 are bound; R14 is hydrogen or R14 designates, together with R3, R6 or R13, an additional bond between the carbon atoms to which R14 and R3 or R6 or R13 are bound; R15 is selected from the group consisting of hydrogen, C1-C4 alkyl, methylene, hydroxy, methoxy, acetoxy, oxo, and xe2x95x90NOR23 wherein R23 is hydrogen or C1-C3 alkyl, or R15 designates, together with R4, an additional bond between the carbon atoms to which R15 and R4 are bound; R16 is selected from the group consisting of hydrogen, C1-C3 alkyl, methylene, hydroxy, methoxy, oxo and xe2x95x90NOR24 wherein R24 is hydrogen or C1-C3 alkyl, or R16 designates, together with R17, an additional bond between the carbon atoms to which R16 and R17 are bound; R17 is hydrogen or R17 designates, together with R16, an additional bond between the carbon atoms to which R17 and R16 are bound; R18 and R19 are independently hydrogen or fluoro; R25 is selected from the group consisting of C1-4alkyl, methylene, hydroxy and oxo; A is a carbon atom or a nitrogen atom; when A is a carbon atom, R7 is selected from the group consisting of hydrogen, hydroxy and fluoro, and R8 is selected from the group consisting of hydrogen, C1-C4 alkyl, methylene and halogen, or R7 designates, together with R8, an additional bond between the carbon atoms to which R7 and R8 are bound; R20 is selected from the group consisting of C1-C4 alkyl, trifluoromethyl and C3-C6 cycloalkyl and R21 is selected from the group consisting of C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkyl containing up to three halogen atoms, methoxymethyl, acetoxymethyl, and C3-C6 cycloalkyl, or R20 and R21, together with the carbon atom to which they are bound, form a C3-C6 cycloalkyl ring; and when A is a nitrogen atom, R7 designates a lone pair of electrons and R8 is selected from the group consisting of hydrogen, C1-C4 alkyl and oxo; R20 and R21 are, independently, C1-C4 alkyl or C3-C6 cycloalkyl; provided that the compound of formula (I) does not have any cumulated double bonds and further provided that the compound is not one of the following compounds:
Cholest-7-ene-3xcex2-ol;
4-Methylcholest-7-ene-3xcex2-ol;
4-Ethylcholest-7-ene-3xcex2-ol;
4,4-Dimethylcholest-7-ene-3xcex2-ol;
4xcex1-Methyl-4xcex2-ethylcholest-7-ene-3xcex2-ol;
4xcex1-Ethyl-4xcex2-methylcholest-7-ene-3xcex2-ol;
4,4-Diethylcholest-7-ene-3xcex2-ol;
4-Propylcholest-7-ene-3xcex2-ol;
4-Butylcholest-7-ene-3xcex2-ol;
4-Isobutylcholest-7-ene-3xcex2-ol;
4,4-Tetramethylenecholest-7-ene-3xcex2-ol;
4,4-Pentamethylenecholest-7-ene-3xcex2-ol;
Cholest-8-ene-3xcex2-ol;
4-Methylcholest-8-ene-3xcex2-ol;
4-Ethylcholest-8-ene-3xcex2-ol;
4,4-Dimethylcholest-8-ene-3xcex2-ol;
4xcex1-Methyl-4xcex2-ethylcholest-8-ene-3xcex2-ol;
4xcex1-Ethyl-4xcex2-methylcholest-8-ene-3xcex2-ol;
4,4-Diethylcholest-8-ene-3xcex2-ol;
4-Propylcholest-8-ene-3xcex2-ol;
4-Butylcholest-8-ene-3xcex2-ol;
4-Isobutylcholest-8-ene-3xcex2-ol;
4,4-Tetramethylenecholest-8-ene-3xcex2-ol;
4,4-Pentamethylenecholest-8-ene-3xcex2-ol;
Cholest-8(14)-ene-3xcex2-ol;
4-Methylcholest-8(14)-ene-3xcex2-ol;
4-Ethylcholest-8(14)-ene-3xcex2-ol;
4,4-Dimethylcholest-8(14)-ene-3xcex2-ol;
4xcex1-Methyl-4xcex2-ethylcholest-8(14)-ene-3xcex2-ol;
4xcex1-Ethyl-4xcex2-methylcholest-8(14)-ene-3xcex2-ol;
4,4-Diethylcholest-8(14)-ene-3xcex2-ol;
4-Propylcholest-8(14)-ene-3xcex2-ol;
4-Butylcholest-8(14)-ene-3xcex2-ol;
4-Isobutylcholest-8(14)-ene-3xcex2-ol;
4,4-Tetramethylenecholest-8(14)-ene-3xcex2-ol;
4,4-Pentamethylenecholest-8(14)-ene-3xcex2-ol;
Cholesta-8,14-diene-3xcex2-ol;
4-Methylcholesta-8,14-diene-3xcex2-ol;
4-Ethylcholesta-8,14-diene-3xcex2-ol;
4,4-Dimethylcholesta-8,14-diene-3xcex2-ol;
4xcex1-Methyl-4xcex2-ethylchlolesta-8,14-diene-3xcex2-ol;
4xcex1-Ethyl-4xcex2-methylcholesta-8,14-diene-3xcex2-ol;
4,4-Diethylcholesta-8,14-diene-3xcex2-ol;
4-Propylcholesta-8,14-diene-3xcex2-ol;
4-Butylcholesta-8,14-diene-3xcex2-ol;
4-Isobutylcholesta-8,14-diene-3xcex2-ol;
4,4-Tetramethylenecholesta-8,14-diene-3xcex2-ol;
4,4-Pentamethylenecholesta-8,14-diene-3xcex2-ol;
Cholesta-8,24-diene-3xcex2-ol;
4-Methylcholesta-8,24-diene-3xcex2-ol;
4-Ethylcholesta-8,24-diene-3xcex2-ol;
4,4-Dimethylcholesta-8,24-diene-3xcex2-ol;
4xcex1-Methyl-4xcex2-ethylcholesta-8,24-diene-3xcex2-ol;
4xcex1-Ethyl-4xcex2-methylcholesta-8,24-diene-3xcex2-ol;
4,4-Diethylcholesta-8,24-diene-3xcex2-ol;
4-Propylcholesta-8,24-diene-3xcex2-ol;
4-Butylcholesta-8,24-diene-3xcex2-ol;
4-Isobutylcholesta-8,24-diene-3xcex2-ol;
4,4-Tetramethylenecholesta-8,24-diene-3xcex2-ol;
4,4-Pentamethylenecholesta-8,24-diene-3xcex2-ol;
Cholesta-8,14,24-triene-3xcex2-ol;
4-Methylcholesta-8,14,24-triene-3xcex2-ol;
4-Ethylcholesta-8,14,24-triene-3xcex2-ol;
4,4-Dimethylcholesta-8,14,24-triene-3xcex2-ol;
4xcex1-Methyl-4xcex2ethylcholesta-8,14,24-triene-3xcex2-ol;
4xcex1-Ethyl-4xcex2methylcholesta-8,14,24-triene-3xcex2-ol;
4,4-Diethylcholesta-8,14,24-triene-3xcex2-ol;
4-Propylcholesta-8,14,24-triene-3xcex2-ol
4-Butylcholesta-8,14,24-triene-3xcex2-ol;
4-Isobutylcholesta-8,14,24-triene-3xcex2-ol;
4,4-Tetramethylenecholesta-8,14,24-triene-3xcex2-ol; and
4,4-Pentamethylenecholesta-8,14,24-triene-3xcex2-ol;
and esters and ethers thereof, and further provided that the compound of formula (I) is not a compound of formula (II) 
wherein R1* and R2*, independently, are selected from the group consisting of hydrogen, branched or unbranched C1-C6 alkyl which may be substituted by halogen or hydroxy or wherein R1* and R2*, together with the carbon atom to which they are bound, form a cyclopentane ring or a cyclohexane ring; R13* and R14* together designate an additional bond between the carbon atoms to which they are bound in which case R3* is hydrogen and R6* and R5* are either hydrogen or together they designate an additional bond between the carbon atoms to which they are bound; or R3* and R14* together designate an additional are either hydrogen or together they designate an additional bond between the carbon atoms to which they are bound; or R6* and R14* together designate an additional bond between the carbon atoms to which they are bound in which case R13*, R3* and R5* are all hydrogen; R8* and R7* are hydrogen or together they designate an additional bond between the carbon atoms to which they are bound; and B* is either hydrogen or an acyl group, including a sulphonyl group or a phosphonyl group, or a group which together with the remaining part of the molecule forms an ether.
In seperate and more specific embodiments, the compound of formula (I) above is a compound wherein: R1 and R2 are both hydrogen; one of R1 and R2 is hydrogen while the other is methyl; wherein R1 and R2 are both methyl; R1 is branched or unbranched C1-C6 alkyl, optionally substituted by halogen, hydroxy or cyano; R2 is branched or unbranched C1-C6 alkyl, optionally substituted by halogen, hydroxy or cyano; R1 and R2 together designate methylene wherein R1 and R2, together with the carbon atom to which they are bound, form a cyclopropane ring; R1 and R2, together with the carbon atom to which they are bound, form a cyclopentane ring; R1 and R2, together with the carbon atom to which they are bound, form a cyclohexane ring.
In further specific embodiments, the compound of formula (I) above is a compound wherein R3 is hydrogen; methylene; hydroxy; methoxy or acetoxy; halogen; oxo; or xe2x95x90NOH. In one embodiment, R3 is xe2x95x90NOR26 wherein R26 is C1-C3 alkyl. In further specific embodiments, R3 is hydroxy and C1 -C4 alkyl bound to the same carbon atom of the sterol skeleton; R3, together with R9, designates an additional bond between the carbon atoms to which R3 and R9 are bound; and R3, together with R14, designates an additional bond between the carbon atoms to which R3 and R14 are bound;.
In specific embodiments, the compound of formula (I) above is a compound wherein R4 is one of hydrogen, methylene, hydroxy, methoxy, acetoxy, oxo, xe2x95x90NOH, xe2x95x90NOR27, wherein R27 is C1-C3 alkyl. In further embodiments, the compound of formula (I) above is a compound wherein R4 is hydroxy and C1-C4 alkyl bound to the same carbon atom of the sterol skeleton; R4, together with R13, designates an additional bond between the carbon atoms to which R4 and R13 are bound; or R4, together with R15, designates an additional bond between the carbon atoms to which R4 and R15 are bound.
In specific embodiments, the compound of formula (I) above is a compound wherein R5 is one of hydrogen, C1-C4 alkyl, methylene, hydroxy; methoxy; oxo; xe2x95x90NOH; or R5 is xe2x95x90NOR22, wherein R22 is C1-C3 alkyl; or R5, together with R6, designates an additional bond between the carbon atoms to which R5 and R6 are bound.
In specific embodiments, the compound of formula (I) above is a compound wherein R6 is hydrogen; or wherein R6, together with R14, designates an additional bond between the carbon atoms to which R6 and
R14 are bound.
In specific embodiments, the compound of formula (I) above is a compound wherein R9 is hydrogen, or wherein R9, together with R10, designates an additional bond between the carbon atoms to which R9 and
R10 are bound.
In another specific embodiment, the compound of formula (1) above is a compound wherein R10 is hydrogen.
In another specific embodiment, the compound of formula (I) above is a compound wherein R11 is one of hydroxy; alkoxy, aralkyloxy, alkoxyalkoxy or alkanoyloxyalkyl, each group comprising a total of up to 10 carbon atoms, preferably up to 8 carbon atoms; C1-C4 alkoxy; methoxy; ethoxy; CH3OCH2Oxe2x80x94; pivaloyloxymethoxy; an acyloxy group derived from an acid having from 1 to 20 carbon atoms; an acyloxy group selected from the group consisting of acetoxy, benzoyloxy, pivaloyloxy, butyryloxy, nicotinoyloxy, isonicotinoyloxy, hemi succinoyloxy, hemi glutaroyloxy, butylcarbamoyloxy, phenylcarbamoyloxy, butoxy carbonyloxy, tert-butoxycarbonyloxy and ethoxycarbonyloxy; sulphonyloxy; phosphonyloxy; oxo; or xe2x95x90NOH. In another related embodiment, the compound of formula (I) above is a compound wherein R11 is xe2x95x90NOR28, wherein R28 is C1-C3 alkyl. In further embodiments, R11 is halogen; or R11 is hydroxy and C1-C4 alkyl bound to the same carbon atom of the sterol skeleton; or R11, together with R12, designates an additional bond between the carbon atoms to which R11 and R12 are bound.
In further embodiments, R12 is one of hydrogen.; C1-C3 alkyl; C1-C3 alkoxy; or halogen.
In another embodiments, the compound of formula (I) above is a compound wherein R13 is hydrogen; or wherein R13, together with R14, designates an additional bond between the carbon atoms to which R13 and R14 are bound.
In further embodiments, the compound of formula (I) above is a compound wherein R14 is hydrogen.
In another embodiment, the compound of formula (I) above is a compound wherein R15 is one of hydrogen; C1-C4 alkyl; methylene; hydroxy; R15 is methoxy or acetoxy; oxo; xe2x95x90NOH; or R15 is xe2x95x90NOR23, wherein R23 is C1-C3 alkyl.
In further embodiments, the compound of formula (I) above is a compound wherein R16 is one of hydrogen; C1-C3 alkyl; methylene; hydroxy; methoxy; oxo; or xe2x95x90NOH; or a compound wherein R16 is xe2x95x90NOR24, wherein R24 is C1-C3 alkyl; or wherein R16, together with R17, designates an additional bond between the carbon atoms to which R16 and R17 are bound.
In another embodiment, the compound of formula (I) above is a compound wherein R17 is hydrogen or hydroxy.
In another embodiment, the compound of formula (I) above is a compound wherein R18 and R19 are both hydrogen; or wherein R18 and R19 are both fluoro; or one of R18 and R19 is fluoro and the other is hydrogen.
In another embodiment, the compound of formula (I) above is a compound wherein R25 is one of hydrogen; C1-C4 alkyl; methylene; hydroxy; or oxo.
In further related embodiments, the compound of formula (I) above is a compound wherein A is a carbon atom; A is a carbon atom and R7 is hydrogen; A is a carbon atom R7 is hydroxy; A is a carbon atom R7 is fluoro; A is a carbon atom R7, together with R8, designates an additional bond between the carbon atoms to which R7 and R8 are bound; A is a carbon atom R8 is hydrogen; A is a carbon atom R8 is C1-C4 alkyl; A is a carbon atom R8 is methylene; A is a carbon atom R8 is halogen; A is a carbon atom R20 is C1-C4 alkyl; A is a carbon atom R20 is trifluoromethyl; A is a carbon atom R20 is C3-C6 cycloalkyl; A is a carbon atom R21 is C1-C4 alkyl; A is a carbon atom R21 is C1-C4 hydroxyalkyl; A is a carbon atom R21 is C1-C4 haloalkyl containing up to three halogen atoms; A is a carbon atom R21 is acetoxymethyl; A is a carbon atom R21 is methoxymethyl; A is a carbon atom and R21 is C3-C6 cycloalkyl; A is a carbon atom and R20 and R21, together with the carbon atom to which they are bound, form a C3-C6 cycloalkyl ring, preferably a cyclopropyl ring, a cyclopentyl ring or a cyclohexyl ring; A is a nitrogen and R7 designates a lone pair of electrons.
In another more specific embodiment, the compound of formula (I) above is a compound wherein A is a nitrogen atom, R7 designates a lone pair of electrons and R8 is hydrogen; A is a nitrogen atom, R7 designates a lone pair of electrons and R8 is C1-C4 alkyl; A is a nitrogen atom, R7 designates a lone pair of electrons and R8 is oxo; or A is a nitrogen atom, R7 designates a lone pair of electrons and R20 and R21, independently, are selected from the group consisting of C1-C4 alkyl, cyclopropyl, cyclopentyl and cyclohexyl.
In a further aspect, the present invention relates to the use of a compound of formula (I) above as a medicament, in particular as a medicament for use in the regulation of meiosis. The compound may be used neat or in the form of a liquid or solid composition containing auxiliary ingredients conventionally used in the art.
The presence of a diffusible meiosis regulating substance was first described by Byskov et al. in a culture system of fetal mouse gonads (Byskov, A G et al. Dev Biol 52 (1976) 193-200). A meiosis activating substance (MAS) was secreted by the fetal mouse ovary in which meiosis was ongoing, and a meiosis preventing substance (MPS) was released from the morphologically differentiated testis with resting, non-meiotic germ cells. It was suggested that the relative concentrations of MAS and MPS regulated the beginning, arrest and resumption of meiosis in the male and in the female germ cells (Byskov, A G et al. in The Physiology of Reproduction (eds. Knobil, E and Neill, J D, Raven Press, New York (1994)). A recent article (Byskov, A G et al. Nature 374 (1995) 559-562) describes the isolation from bull testes and from human follicular fluid of certain sterols that activate oocyte meiosis. Unfortunately, these sterols are rather labile and utilization of the interesting finding would thus be greatly facilitated if more stable meiosis activating compounds were available.
In the present context, the expression xe2x80x9cregulating the meiosisxe2x80x9d is used to indicate that compounds of the invention can be used for stimulating the meiosis, including in vitro, in vivo, or ex vivo use. Thus, the compounds which agonists of a naturally occurring meiosis activating substance, can be used in the treatment of infertility which is due to insufficient stimulation of meiosis in females and in males. Other compounds of the invention, which are antagonists of a naturally occurring meiosis activating substance, can be used for regulating meiosis, preferably in vivo, such that they are suitable as contraceptives. In this case the xe2x80x9cregulationxe2x80x9d means partial or total inhibition.
In one aspect of the invention, compounds of formula (I) above are useful in a method for regulation of the meiosis of an oocyte, in particular a mammalian oocyte, more particularly a human oocyte.
In one embodiment, a compound of formula (J) above is useful in methods for stimulating the meiosis of an oocyte, in particular a mammalian oocyte, more particularly a human oocyte. In another embodiment, a compound of formula (I) above is useful in methods for inhibiting the meiosis of an oocyte, in particular a mammalian oocyte, more particularly a human oocyte.
In a related aspect, the present invention relates to the use of a compound of formula (I) above in the regulation of the meiosis of a male germ cell, in particular a mammalian male germ cell, more particularly a human male germ cell. In one embodiment, a compound of formula (I) above is useful in methods for stimulating of the meiosis of a male germ cell, in particular a mammalian male germ cell, more particularly a human male germ cell. In another embodiment, a compound of formula (I) above is useful in a method for inhibiting the meiosis of a male germ cell, in particular a mammalian male germ cell, more particularly a human male germ cell.
In one aspect, the present invention encompasses methods of regulating meiosis in a mammalian germ cell, comprising administering an effective amount of a compound of formula (I) above to a germ cell in need of such a treatment. In one aspect, the compound is administered to the germ cell by administering the compound to a mammal hosting said cell. In specific embodiments, the germ cell is an oocyte or a male germ cell. In more specific embodiments, the compound is administered to the oocyte ex vivo. In another specific embodiment, the compound is administered to immature male germ cells in vitro to produce mature male germ cells. In a further specific embodiment, the immature male germ cells are contained in testicular tissue.
Methods of Controlling Meiosis
Controlling of meiosis is achieved as described in Examples 41-46 (below) using the compounds described herein that stimulate or induce meiosis (agonists of the naturally occurring meiosis activating sterols), or the compounds described herein that counteract or inhibits meiosis (antagonist of the naturally occurring meiosis activating sterols).
The timing and the compound""s effect is pivotal for obtaining the desired objective whether this is to treat or relieve infertility or whether this is to obtain a safe and efficacious novel contraceptive method.
Definitions
As used in the present description and claims, the expression C1-C3 alkyl designates an alkyl group having from one to three carbon atoms; preferred examples are methyl, ethyl and propyl, more preferred methyl and ethyl. Similarly, the expression C1-C4 alkyl designates an alkyl group having from one to four carbon atoms; preferred examples are methyl, ethyl, propyl, isopropyl and butyl, more preferred methyl and ethyl. The expression C1-C6 alkyl designates an alkyl group having from one to six carbon atoms; preferred examples are methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl, more preferred methyl, ethyl, propyl, isopropyl, butyl and tert-butyl, still more preferred methyl and ethyl.
As used in the present description and claims, the expression C1-C3 alkoxy designates an alkoxy group having from one to three carbon atoms; preferred examples are methoxy, ethoxy and propoxy, more preferred methoxy and ethoxy.
As used in the present description and claims, the expression halogen preferably designates fluoro and chloro, more preferred fluoro.
The compounds of the invention have a number of chiral centers in the molecule and thus exist in several isomeric forms. All these isomeric forms and mixtures thereof are within the scope of the invention.
The compounds of the present invention will influence the meiosis in oocytes as well as in male germ cells.
General
The existence of a meiosis inducing substance in nature has been known for some time. However, until recently the identity of the meiosis inducing substance or substances was unknown. The possibility of being able to influence the meiosis are several. According to a preferred embodiment of the present invention, the instant compounds are used to stimulate the meiosis. According to another preferred embodiment of the present invention, the instant compounds are used to stimulate the meiosis in humans. Thus, these compounds are promising as new fertility regulating agents without the usual side effect on the somatic cells which are known from the hitherto used hormonal contraceptives which are based on estrogens and/or gestagens.
For use as a contraceptive agent in females, a meiosis inducing substance can be administered so as to prematurely induce resumption of meiosis in oocytes while they are still in the growing follicle, before the ovulatory peak of gonadotropins occurs. In women, the resumption of the meiosis can, for example, be induced a week after the preceding menstruation has ceased. When ovulated, the resulting overmature oocytes are then most likely not to be fertilized. The normal menstrual cycle is not likely to be affected. In this connection it is important to notice, that the biosynthesis of progesterone in cultured human granulosa cells (somatic cells of the follicle) is not affected by the presence of a meiosis inducing substance whereas the estrogens and gestagens used in the hitherto used hormonal contraceptives do have an adverse effect on the biosynthesis of progesterone.
According to another aspect of this invention, a meiosis inducing substance of the instant invention can be used in the treatment of certain cases of infertility in females, including women, by administration thereof to females who, due to an insufficient own production of meiosis activating substance, are unable to produce mature oocytes. Also, when in vitro fertilization is performed, better results are achieved, when a compound of claim 1 is added to the medium in which the oocytes are kept.
When infertility in males, including men, is caused by an insufficient own production of the meiosis activating substance and thus a lack of mature sperm cells, administration of a compound of the invention may relieve the problem.
As an alternative to the method described above, contraception in females can also be achieved by administration of the instant compound which inhibits meiosis, so that no mature oocytes are produced. Similarly, contraception in males can be achieved by administration of a compound of the instant invention which inhibits the meiosis, so that no mature sperm cells are produced.
The route of administration of compositions containing a compound of the instant invention may be any route which effectively transports the active compound to its site of action. Thus, when the compounds of this invention are to be administered to a mammal, they are conveniently provided in the form of a pharmaceutical composition which comprises at least one compound of the instant invention in connection with a pharmaceutically acceptable carrier. For oral use, such compositions are preferably in the form of capsules or tablets.
From the above it will be understood that the administrative regimen called for will depend on the condition to be treated. Thus, when used in the treatment of infertility the administration may have to take place once only, or for a limited period, e.g. until pregnancy is achieved. When used as a contraceptive, the compounds will either have to be administered continuously or cyclically. When used as a contraceptive by females and not taken continuously, the timing of the administration relative to the ovulation will be important.
Pharmaceutical compositions comprising a compound of the instant invention may further comprise carriers, diluents, absorption enhancers, preservatives, buffers, agents for adjusting the osmotic pressure, tablet disintegrating agents and other ingredients which are conventionally used in the art. Examples of solid carriers are magnesium carbonate, magnesium stearate, dextrin, lactose, sugar, talc, gelatin, pectin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting waxes and cocoa butter.
Liquid compositions include sterile solutions, suspensions and emulsions. Such liquid compositions may be suitable for injection or for use in connection with ex vivo and in vitro fertilization. The liquid compositions may contain other ingredients which are conventionally used in the art, some of which are mentioned in the list above.
Further, a composition for transdermal administration of a compound of this invention may be provided in the form of a patch and a composition for nasal administration may be provided in the form of a nasal spray in liquid or powder form.
The dose of a compound of the invention to be used will be determined by a physician and will depend, inter alia, on the particular compound employed, on the route of administration and on the purpose of the use.
The instant compounds may be synthesized by methods known per se.
The present invention is further illustrated by the following examples which, however, are not to be construed as limiting the scope of protection. The features disclosed in the foregoing description and in the following examples may, in any combination thereof, be material for realizing the invention in diverse forms thereof.